2-Bromo-2-bromomethylglutaronitrile

ABSTRACT

In the synthesis of 3-cyanopyridine from non-heterocyclic starting materials, namely, 2-methyleneglutaronitrile the intermediate 2-bromo-2-bromomethylglutaronitrile is obtained, which intermediate compound is useful as an antibacterial and antifungal agent.

United States Patent [191 Harmetz et al.

I 2-BROMO-2- BROMOMETHYLGLUTARONITRILE [75] Inventors: Ronald Harmetz,Randolph; Roger J. Tull, Metuchen, both of NJ.

[73] Assignee: Merck & C0., lnc., Rahway, NJ.

[22] Filed: Nov. 20, 1973 [21] Appl. No.: 417,647

Related U.S. Application Data [60] Continuation-in-part of Ser. No.131,445, April 5, 1971, abandoned. which is a division of Ser. No.879,519, Nov. 24, 1969, Pat. No. 3,644,380.

[52] U.S. Cl 260/465.7, 260/294.9, 424/304 {51] Int. Cl. C07c 121/20Field of Search 260/4657 [56] References Cited UNITED STATES PATENTS3,562,311 2/1971 McClure 260/4658 R 3,567,759 3/1971 Tullio 260/4658 RFOREIGN PATENTS OR APPLICATIONS 1,097,360 1/1968 United Kingdom 260/4657[4 Mar. 25, 1975 Moyer, et al., J. Org. Chem, 31, 1094-1098.

Kondratenko, ct al., C. A.; 68, (1968), 12440k.

Primary E.\'aminerJ0seph P. Brust Attorney, Agent, or FirmEdmunde D.Riedl; J. Jerome Behan; Rudolph J. Anderson, Jr.

[57] ABSTRACT In the synthesis of 3-cyanopyridine from nonheterocyclicstarting materials, namely, 2

methyleneglutaronitrile the intermediate 2-bromo-2-bromomethylglutaronitrile is obtained, which intermediate compound isuseful as an antibacterial and antifungal agent.

1 Claim, N0 Drawings 1 Z-BROMO-Z-BROMOMETHYLGLUTARONITRILE SUMMARY OFTHE INVENTION This application is a continuationin-part of U.S. Ser. No.l3l,445, filed Apr. 15, l97l and now abandoned which is a division ofU.S. Ser. No. 879,519 filed Nov. 24, I969, now U.S. Pat. No. 3,644,380issued Feb. 22, 1970 and relates to new processes for the preparation ofthat compound. More particularly, it relates to the intermediate2-halo-2-halomethylglutaronitrile, especially the2-bromo-2-bromomethylglutaronitrile, which is an extremely usefulantibacterial and antifungal compound as disclosed in the copendingapplication of Lederer, et al., Ser. No. 102,197 filed Dec. 28, 1970,now U.S. Pat. No. 3,833,731, the disclosure of which is herebyincorporated herein.

BACKGROUND OF THE INVENTION 3-Cyanopyridine (nicotinonitrile) is avaluable intermediate useful in the preparation of nicotinic acid(niacin) and nicotinamide. The novel 2-bromo-2- bromomethylglutaronitrile has activity against bacteria, fungi and algae whenemployed at appropriate levels of concentration and may be used toinhibit growth ofthese organisms. It will be obvious to those skilled inthe art that the required effective concentration will vary withparticular organisms and in particular applications. In general,however, effective fungicidal, bactericidal and algicidal response isobtained when the 2-bromo-2-bromomethylglutaronitriles is employed inconcentrations ranging from 0.5 and 1,000 ppm. (parts per million).

DESCRIPTION OF THE INVENTION The present invention provides afacilemethod for obtaining 3-cyanopyridine (IV) from readily availablestarting materials as seen in the following flow sheet:

cs (II) l RX l NCCH -CH -C-CN R=X (III) I l R- (V) CH X CN R=X (VII) R=H(VI) In accordance with the foregoing flow sheet, 3- cyanopyridine isprepared from 2-methylene glutaronitrile.

2-Methyleneglutaronitrile (ll), prepared by known methods, is reactedwith a compound of the type RX where X is a halogen and R is eitherhydrogen or X. The reaction is a simple addition across a double bondforming III where R is X and V where R is H.

Ill and V are treated with a Lewis acid in a cyclization reaction suchthat the nitrile group farthest from the halomethyl group reacts withthat group, displacing the halogen (X) and forming VI where R is H andVII where R is X.

HR is eliminated from each of these compounds forming the desired3-cyanopyridine. The elimination is carried out by treatment with alkaliin the case where R is equal to halogen and catalytically in the casewhere R is equal to hydrogen.

In accordance with one embodiment of our invention,2-methyleneglutaronitrile is halogenated by reaction with chlorine,bromine or iodine to obtain the corresponding2-halo-2-halomethylglutaronitrile which is then cyclized by reactionwith a Lewis acid and the resulting reaction product is treated with abase to produce the desired 3cyanopyridine.

The halogenation is readily effected by intimately contacting thenitrile with the halogen, preferably at temperatures below about 30C.The reaction can be carried out in the presence of a non-reactivesolvent, although generally we find that a solvent is unnecessary. Thehalogenated product obtained, for example, by passing chlorine throughthe 2- methyleneglutaronitrile while maintaining the reaction mixture ata temperature l520C. can be used directly in the next step; or, ifdesired, can be purified by distillation under reduced pressure.

The cyclization step is effected by heating the intermediate dihalocompound with a Lewis acid. Although any Lewis acid can be used in thisprocess, we prefer to use stannic chloride, aluminum chloride, titaniumchloride, or boron trifluoride etherate since maximum yields of3-cyanopyridine are obtained with these acids under optimum conditions.The cyclization proceeds at temperatures from to 250C. although,generally, we prefer to carry out the reaction at a temperature of to200C. The time required for this step will vary, depending upon thetemperature and the Lewis acid used, but usually the reaction iscomplete in 2 5 hours. Although the reaction can be carried out withouta solvent, we find that it is most conveniently effected in a suitablesolvent medium, preferably one having a boiling point of at least C.Examples of suitable solvents that might be mentioned are nitrobenzeneor halogenated hydrocarbons such as ortho dichlorobenzene. Although thereaction can be effected at atmospheric pressure, we find that betteryields are obtained when the reaction is effected in a sealed vessel.

After completion of the cyclization step, the resulting reaction mixtureis extracted with water to obtain an aqueous solution containing3-halo-3- cyanodihydropyridine which, when treated with a base such asan alkali metal hydroxide, is converted to the desired 3-cyanopyridine.

In a modification of the above steps, 3-cyanopyridine can be prepared inone reaction vessel, without isolating any intermediates and, in fact,preparing the 2- methylcne glutaronitrile itself by the known procedureof dimerizing acrylonitrile with a trialkyl phosphine such astricyclohexyl phosphine in an inert solvent, preferably with a boilingpoint of less than 100C. such as tetrahydrofuran. The2-methyleneglutaronitrile prepared in situ is combined with a halogen,preferably in equimolar amounts to form the 2-halo-2-halomethylglutaronitrile. The solvent is evaporated in vacuo and the residuetreated with a solvent preferably a low boiling one (about 100C) capableof azotroping water from the system, and being non-reactive to Lewisacids. Benzene and toluene are suitable for this purpose. The Lewis acidis added to the residue and the reaction vessel is sealed and heated toaffect the cyclization to 3- cyanopyridine. The reaction can be carriedout at temperatures of 80250C. for 2-5 hours.

In another embodiment of our invention, 2- methyleneglutaronitrile isconverted to 2- halomethylglutaronitrile by hydrohalogenation with ahydrogen halide. The resultant halo compound is cyclized with a Lewisacid to dihydro-3-cyanopyridine. This can be subsequently dehydrogenatedwith heat and a suitable catalyst to the desired 3-cyanopyridine.

The hydrohalogenation step can be carried out without a solvent at atemperature of about 5C. using for example hydrogen chloride in excessof a single molar amount. The recovered 2- halomethylglutaronitrile canbe used as it comes from the reaction vessel or distilled to purify it.

Cyclization of the 2-halomethylglutaronitrile is carried out asdescribed for the 2-halo-2- halomethylglutaronitrile except the reactionmixture, on cooling, is treated with water and extracted with'anon-polar, water immiscible organic solvent which dissolves the dihydro3-cyano' pyridine. Chloroform and ethyl ether are solvents that haveproven tobe of merit. After evaporationof the organic solvent, thedihydro- 3-cyanopyridine can be used as is or purified by vacuumdistillation.

The dihydro-3-cyanopyridine is converted to 3- cyanopyridine bydehydrogenating using a suitable catalyst.

Metallic catalysts, such as the noble metals, have been found to givethe best results. The reaction may also include a hydrogen scavengerwhich chemically absorbs the hydrogen as it is set free by the catalyst.Organic compounds with one or more non-aromatic unsaturations arepreferred, with indene, cyclohexene, or stilbene being particularly goodfor this purpose. The reaction is run at a temperature of from roomtemperature to 150C. in a solvent, inert to reaction at the reactiontemperature. Decalin has been found to be a highly suitable solvent.

The following examples are presented to illustrate the process of thisinvention. They should not be construed as limitations thereof.

EXAMPLE 1 Preparation of 2-chloro-2-chloromethylglutaronitrile 106 gms.(1.0 mole) of 2-methyleneglutaronitrile is placed in a flask, fittedwith a stirrer, calcium chloride drying tube and subsurface gas inlettube. The material is cooled to 1520C. and chlorine gas is added withagitation at such a rate that the temperature does nt exceed 20C. Whenan equimolar amount of chlorine is absorbed, the addition is stopped andthe mixture stirred for an additional hour. The product, 2-chloro-2-chloromethylglutaronitrile (b.p. 136-138 at 1.5 mm) can be purified bydistillation under reduced pressure or can be used in Example 3 below asis.

EXAMPLE 2 Preparation of 2-bromo-2-bromomethylglutaronitrile 106 g. (1.0m.)-2-methyleneglutaronitrile and 160.0 g. (1.0 m.) liquid bromine arecombined and stirred at a temperature of 25-27C. for 3 days. Thereaction mixture is then treated with aqueous sodium bisulfite andextracted with 3 X 100 cc. ethyl ether. The ether extracts are washedwith 3 X 50 cc. aqueous sodium bicarbonate and dried with anhydrousmagnesium sulfate. The ether is filtered to remove the magnesiumsulfate, and evaporated to give crude 2-bromo-2-bromomethylglutaronitrile (m.p. 45-53C) which is purified byrecrystallization from isopropanol yielding pure material m.p. 51.5525C.

lodine may be used in a similar manner as above to yield2-iodo-2-iodomethylglutaronitrile.

EXAMPLE 3 Conversion of 2-chloro-2-chloromethylglutaronitrile to3-cyanopyridine A mixture containing 177 gms. (1.0 mole) of 2-chloro-2-chloromethylglutaronitrile, 260 gms. (1.0 mole) of stannicchloride and 1.0 liters of orthodichlorobenzene is heated at 150C. in asealed reaction vessel for 3 hours. The mixture is then cooled to 1020C. and extracted with 3 X 100 ml. of water to obtain an aqueous Isolution of 3-chloro-3- cyanodihydropyridine. The combined aqueousextracts are made basic with aqueous sodium hydroxide and then extractedwith 3 l00 cc. ether. Evaporation of the ether to dryness andrecrystallization of the residue from petroleum ether gives gms. of3-cyanopyridine.

Following the procedure of the above example using amolar equivalent ofaluminum chloride, titanium chloride or boron trifluoride etherate inplace of stannic chloride, good yields of '3-cyanopyridine are obtained.m.p. 50-51C.

EXAMPLE 4 Conversion of 2-ch1oro-2-chloromethylglutaronitrile to3-cyanopyridine 177 g. (1.0m) of 2-chloro-2- chloromethylglutaronitrileand 260 g. (1.0m) stannic chloride are heated at 150C. for 3 hours. Thereaction mixture is cooled to 05C., made basic with 20 percent sodiumhydroxide to a pH of from 8-11, and extracted with 3 X cc. ethyl ether.The ethyl ether extracts are evaporated to dryness and the residuerecrystallized from petroleum ether to give 3-cyanopyridine.

EXAMPLE 5 Preparation of 2-chloromethylglutaronitrile from2-methyleneglutaronitrile 1.06 gms. (1.0 m.) of2-methyleneglutaronitrile and 1.4 gms. of diethyl amine hydrochlorideare placed in a flask fitted with a stirrer, thermometer, calciumchloride drying tube and subsurface gas inlet tube. The mixture wascooled to O-l0C. and anhydrous hydrogen chloride gas is then admittedthrough the gas inlet tube,

with agitation, until one molar equivalent of hydrogen chloride isabsorbed. The solution is then warmed to 27C. and hydrogen chloride gasaddition is continued for an additional hour. The mixture is dilutedwith 650 ml. of chloroform and extracted with 2 X 150 ml. of 7.5 percentaqueous sodium bicarbonate solution. The combined aqueous extracts areextracted once with 100 ml. of chloroform. The combined chloroformextracts are extracted with 100 ml. of water and then dried overanhydrous magnesium sulfate. The magnesium sulfate drying agent isremoved by filtration and the filtrate evaporated under reduced pressureto remove the chloroform. The residue, which is 2-chloromethylglutaronitrile, can be purified by distillation underreduced pressure or used as is in the next step. The product has aboiling point of 105C. at 0.08 mm. mercury pressure.

EXAMPLE 6 Conversion of 2-chloromethylglutaronitrile todihydro-3-cyanopyridine A mixture containing 143 gms. (1.0 mole) of 2-chloromethylglutaronitrile, 260 gms. (1.0 mole) of stannic chloride and1 liter of nitrobenzene is heated at 175C. in a sealed reaction vesselfor 3 hours. The reaction mixture is cooled to l020C. and extracted with3 X 200 ml. of dilute aqueous hydrochloric acid. The combined aqueousextracts are made basic with percent sodium hydroxide and then extractedwith 3 X 100 cc. benzene. Evaporation of the benzene extracts affordsdihydro-3-cyanopyridine which can be further purified by distillationunder reduced pressure or used in its present purity as described inExample 8.

EXAMPLE 7 Conversion of 2-chloromethylglutaronitrile todihydro-3-cyanopyridine 143 g. (1.0 rn.) of 2-chloromethylglutaronitrileand 260 g. (1.0 m.) stannic chloride are heated at 150C. for 3 hours.The reaction mixture is cooled, made basic with 20 percent aqueoussodium hydroxide and extractcd with 3 X 100 cc. benzene. Evaporation ofthe benzene extract yields crude dihydro-3-cyanopyridine which can beused as is in the next example or can be further purified bydistillation under reduced pressure.

Following the procedure of Example 4, but using aluminum chloride,titanium tetrachloride, or boron trifluoride etherate in place ofstannic chloride, there is produced dihydro-3-cyanopyridine in ananalagous manner.

EXAMPLE 8 Conversion of dihydro-3-cyanopyridine to 3-cyanopyridinerecrystallization of the residue from petroleum ether gives3-cyanopyridine. m.p. 50-5lC.

EXAMPLE 9 Prepartion of 3-cyanopyridine directly from acrylonitrile g.(2.26 m.) acrylonitrile and 200 ml. tetrahydrofuran are combined withstirring. The mixture is heated to reflux and 8 g. (.029 m.)tricyclohexylphosphine dis solved in 50 ml. oftetrahydrofuran is slowlyadded over 3 hours maintaining the solution at reflux. When the additionis complete, the solution is refluxed an additional hour and then cooledto l520C. Chlorine is bubbled into the reaction until one molarequivalent is added. The solvent is removed in vacuo and benzene isadded with stirring, and evaporated to remove any traces of waterpresent. Stannic chloride (286 g. 1.1 m.) is added to the residue, thereaction vessel is sealed and heated to C. for 3 hours. The reactionmixture is cooled, made basic with 20 percent aqueous sodium hydroxideand extracted with ether. The ether extracts are dried with anhydrousmagnesium sulfate, filtered and evaporated. The residue isrecrystallized from petroleum ether to recover 3-cyanopyridine. m.p. 50-51C What is claimed is:

l. 2-Bromo-2-bromomethylglutaronitrile.

1. 2-BROMO-2-BROMOMETHYLGLUTARONITRILE.